Abstracts

Recent studies indicate that inhibitors of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase have neuroprotective properties against stroke, which occur through mechanisms incidental to the lipid-lowering effects of these agents. Since status epilepticus frequently results in neuronal injury, we investigated whether the HMG CoA reductase inhibitors, simvastatin and atorvastatin, would provide neuroprotection against CA1 depolarization-induced injury. Using paired rat hippocampal slices, we monitored the CA1 orthodromic and antidromic population spike (PS) amplitude during depolarization injury with and without statin treatment. To induce depolarization injury, slices were exposed to 25 mM KCl for 8 min. Treatment with either 100 [mu]M simvastatin or 100 [mu]M atorvastatin was begun 30 minutes prior to KCl exposure and continued for the first 15 min. of recovery. Simvastatin, an HMG CoA reductase inhibitor, provided robust neuroprotection of CA1 PS amplitude in hippocampal slices subjected to depolarization-induced injury. Slices exposed to 25 mM KCl demonstrated rapid loss of evoked response with a mean CA1 orthodromic and antidromic recovery of only 9% [plusmn] 3 and 11% [plusmn] 2, respectively. Treatment with simvastatin (100 [mu]M) provided significant protection against this depolarization injury with CA1 orthodromic and antidromic PS amplitude recovering to 94% [plusmn] 3 and 95% [plusmn] 3. Treatment with 100 [mu]M simvastatin during depolarization injury also produced significant recovery of mean excitatory post-synaptic potential slope (96% [plusmn] 4) after depolarization when compared to paired, unmedicated slices which did not recover (0% [plusmn] 0). Mean fiber volley responses were somewhat resistant to depolarization injury with a mean recovery of 33% [plusmn] 3 in paired, unmedicated slices. In contrast, treatment with simvastatin showed full recovery with a mean 100% [plusmn] 0. The EC50 for CA1 orthodromic and antidromic protection with simvastatin was 43 [mu]M and 41 [mu]M. In addition, we also assessed the neuroprotective efficacy of atorvastatin against depolarization injury. Treatment with atorvastatin (100 [mu]M) also provided significant protection against this depolarization injury with CA1 orthodromic and antidromic PS amplitude recovering to 92% [plusmn] 4 and 93% [plusmn] 3, while unmedicated slices recovered only a mean 11% [plusmn] 2 and 12% [plusmn] 3, respectively. These studies demonstrate that HMG CoA reductase inhibitors provide neuroprotection against CA1 depolarization injury. In addition, these data suggest that the use of these agents may provide a useful strategy in the prevention of brain injury during status epilepticus. (Supported by VA Research Service and the UCLA Brain Injury Research Center.)